Control of Postnatal SVZ Neurogenesis via Cholinergic Circuit Activity

 描述（由申请人提供）：尽管生物医学科学取得了最新进展，但患有神经精神疾病的患者的有效治疗选择仍然有限。虽然大多数人类病例的潜在病因学和病理生理学仍不清楚，但越来越清楚的是，早期神经发育缺陷可能是日后生活中行为后遗症的一个因素。最近，在人类神经精神疾病的小鼠模型中已经描述了神经祖细胞增殖和分化异常。出生后啮齿动物侧脑室周围的脑室下区（SVZ）龛是一个专门的环境，容纳GFAP+星形胶质细胞作为神经干细胞（NSC），主要产生GABA能中间神经元。出生后SVZ神经发生受NSC-intrinsic机制调节，与细胞外/生态位驱动的线索相互作用。一般认为，这些局部效应是维持神经发生的原因，尽管行为模式和疾病状态已经指出了更高水平调节的可能性。目前尚不清楚神经元组或离散神经回路的活动状态是否可以直接控制出生后SVZ神经发生。我们已经确定了乙酰胆碱（ACh）释放神经末梢进入SVZ龛。我们的初步研究结果揭示了一个以前未描述的胆碱能神经元的人口，直接投射到SVZ神经干细胞的过程。光遗传刺激或抑制这些新的胆碱能神经元导致可测量的电流诱导SVZ神经干细胞和并发的神经发生率的变化。我们计划通过确定以下内容来进一步探索这些观察结果：1）哪些更高级别的大脑区域提供兴奋性驱动以诱导SVZ中的ACh释放; 2）SVZ NSC中ACh激活下游所需的分子机制是什么以促进神经发生;以及3）哪些是SVZ利基细胞结构/组织，可以将神经元放电频率转化为NSC增殖和增加神经发生。我们的研究旨在探讨胆碱能神经元的神经元活动与出生后SVZ NSC增殖之间的直接联系。为了使这个研究问题易于处理，我们开发了新的小鼠试剂，以及光遗传学和实时成像平台，以直接测量神经元活动模式和SVZ神经发生之间的相互作用。我们相信，这些发现将产生积极的影响，垂直推进我们的功能理解出生后SVZ神经发生控制电路水平的活动，具有潜在的重要意义胆碱能电路功能障碍的神经精神疾病。

 DESCRIPTION (provided by applicant): Despite recent advances in biomedical sciences, effective treatment options remain limited for patients suffering from neuropsychiatric diseases. While the underlying etiology and pathophysiology remain unclear for majority of the human cases, it has become increasingly clear that early neurodevelopmental defects can be a contributor to behavioral sequelae later in life. Recently, neural progenitor proliferation and differentiation abnormalities have been described in mouse models of human neuropsychiatric disorders. The postnatal rodent subventricular zone (SVZ) niche around the lateral brain ventricles is a specialized environment housing GFAP+ astrocytes functioning as neural stem cells (NSCs), producing mainly GABAergic interneurons. Postnatal SVZ neurogenesis is regulated by NSC-intrinsic mechanisms, interacting with extracellular/niche-driven cues. It is generally believed that these local effects are responsible for sustaining neurogenesis, though behavioral paradigms and disease states have pointed to possibilities for higher-level modulation. It is currently unclear if activity states from groups of neurons, or discrete neural circuits can directly control postnatal SVZ neurogenesis. We have identified acetylcholine (ACh) release by neuronal terminals into the SVZ niche. Our preliminary results have uncovered a previously undescribed population of cholinergic neurons, projecting their processes directly onto SVZ NSCs. Optogenetic stimulation or inhibition of these novel cholinergic neurons resulted in measurable electrical current induction in SVZ NSCs and concurrent changes in the rates of neurogenesis. We plan to further explore these observations by determining the following: 1) which higher-level brain regions provide excitatory drive to induce ACh release in the SVZ; 2) what are the molecular mechanisms required in SVZ NSCs downstream of ACh activation to promote neurogenesis; and 3) which are the SVZ niche cellular structures/organizations that can transform neuronal firing frequencies into NSC proliferation and increased neurogenesis. Our study proposes to explore a direct connection between neuronal activity from cholinergic neurons and postnatal SVZ NSC proliferation. To make this research question tractable, we have developed new mouse reagents, as well as optogenetic and live-imaging platforms to directly measure the interactions between neuronal activity patterns and SVZ neurogenesis. We believe these findings will have a positive impact by vertically advancing our functional understanding of postnatal SVZ neurogenesis control by circuit-level activity, with potentially important implications for cholinergic circuit dysfunctionin neuropsychiatric diseases.